Functional Vascular Progenitors from Na?ve Human iPSC Stem cell treatments for pediatric and adult ischemic disorders such as cerebro-vascular stroke, sickle cell disease, and diabetic retinopathy ultimately require not only the regeneration of damaged myocardium, brain, hematopoietic, and retinal tissues, but also the reconstruction of the defective vascular niche that instigated the initial disease to begin with. The human vasculature normally arises from highly prolific embryonic angioblasts or vascular progenitors (VP) that differentiate into vascular endothelial cells and pericytes during early development. Such prolific embryo-like VP are rare or non-existent in the adult. Furthermore, although circulating adult endothelial progenitor cells (EPC) have been proposed for vascular cellular therapies, such EPC are not only limited in multipotency and expansion, but also functionally defective in diseases such as diabetes. If ischemic acellular capillaries could be efficiently repaired with autologous or HLA- matched embryonic vascular/pericytic progenitors, end stage vascular diseases such as diabetes and cardiac ischemia could be reversed. One solution would be to differentiate human induced pluripotent stem cells (hiPSC) into VP that possess highly prolific embryo-like endothelial- mesenchymal-pericytic potential for regenerating diseased tissues. However, this goal is currently limited by the poor efficiency and variability of directed vascular differentiation from hiPSC. It will be necessary to first generate high-quality clinical grade hiPSC via safer non-integrating, nonviral derivation methods. In this project, we will accomplish this goal by efficiently reprogramming a patient's own blood cells to a novel high quality state of pluripotency called the na?ve ground state that resembles mouse embryonic stem cells (ESC). Na?ve human iPSC (N-hiPSC) possess more versatile abilities than conventional human ESC and hiPSC including more rapid expansion in culture, greater differentiation potencies, and a higher capacity to be genetically manipulated by gene targeting with plasmid-based homologous recombination. We will generate and differentiate N-hiPSC, and specifically test for their capacity to undergo gene targeting and to produce functional embryonic VP that functionally integrate into ischemic tissues for future cell therapies. Finally, we will conduct detailed comparative epigenetic analyses of na?ve and conventional hiPSC and their differentiated VP progeny to elucidate differential CpG methylation and histone architectures. We propose that patient-specific na?ve hiPSC will ultimately provide greater versatility for cellular and gene therapies for pediatric and adult regenerative medicine.